Hypertension is a major risk factor for cerebrovascular disease and stroke, and a leading contributor to Alzheimer's disease and dementia. Thus, hypertension has an enormous negative impact on the brain. Hypertension-induced changes and end-organ damage to vascular muscle underlie many forms of cerebrovascular disease with diverse consequences. Angiotensin II (Ang II) plays a fundamental role during hypertension, promotes atherosclerosis, and contributes to vascular disease in the presence of many cardiovascular risk factors. The cerebral circulation is particularly sensitive to the detrimental effects of Ang II. A major barrier to progress in preventing cerebrovascular disease has been our limited understanding of endogenous molecules that protect the brain from vascular disease. Preliminary data generated in collaboration with Project 1 suggest that the transcription factor peroxisome proliferator-activated receptor-y (PPARy) plays a major protective role in the cerebral circulation. Using novel mouse models to define cell-specific mechanisms, the overall goal is to examine the role of PPARy In smooth muscle in the cerebral circulation under normal conditions and in Ang Il-dependent models of disease. Two major endpoints related to vascular muscle will be studied - regulation of vascular tone and inward remodeling. Aim 1 examines the hypothesis that PPARy in smooth muscle affects regulation of vascular tone and protects against Ang ll induced vascular dysfunction. Aim 1 will also determine if vascular dysfunction following interference with PPARy is mediated by oxidative stress and/or rho kinase and whether increased expression of wild-type PPARy or expression of a constitutively active form of PPARy protects against Ang ll-induced vascular dysfunction. Aim 2 examines the hypothesis that PPARy in smooth muscle protects against inward remodeling and hypertrophy in resistance vessels in vivo and examines mechanisms involved. Preliminary data support these Alms and suggest that interference with PPARy in vascular muscle mimics effects of Ang II in cerebral blood vessels. Thus, mechanistic studies will be performed in resistance vessels supplying brain where the negative impact of hypertension is great and where our preliminary data suggest PPARy normally plays a prominent protective role. This highly collaborative Project fits well with Program-wide themes including mechanisms of cardiovascular protection and cell-specific effects of PPARy.